ACS Medicinal Chemistry Letters p. 80 - 85 (2019)
Update date:2022-08-12
Topics:
Schnute, Mark E.
Benoit, Stephen E.
Buchler, Ingrid P.
Caspers, Nicole
Grapperhaus, Margaret L.
Han, Seungil
Hotchandani, Rajeev
Huang, Nelson
Hughes, Robert O.
Juba, Brian M.
Kim, Kyung-Hee
Liu, Erica
McCarthy, Erin
Messing, Dean
Miyashiro, Joy S.
Mohan, Shashi
O'Connell, Thomas N.
Ohren, Jeffrey F.
Parikh, Mihir D.
Schmidt, Michelle
Selness, Shaun R.
Springer, John R.
Thanabal, Venkataraman
Trujillo, John I.
Walker, Daniel P.
Wan, Zhao-Kui
Withka, Jane M.
Wittwer, Arthur J.
Wood, Nancy L.
Xing, Li
Zapf, Christoph W.
Douhan, John
Potent covalent inhibitors of Bruton's tyrosine kinase (BTK) based on an aminopyrazole carboxamide scaffold have been identified. Compared to acrylamide-based covalent reactive groups leading to irreversible protein adducts, cyanamide-based reversible-covalent inhibitors provided the highest combined BTK potency and EGFR selectivity. The cyanamide covalent mechanism with BTK was confirmed through enzyme kinetic, NMR, MS, and X-ray crystallographic studies. The lead cyanamide-based inhibitors demonstrated excellent kinome selectivity and rat pharmacokinetic properties.
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